Tako-Tsubo Cardiomyopathy

International Journal of Cardiology 124 (2008) 32 – 39 www.elsevier.com/locate/ijcard

Tako-Tsubo Cardiomyopathy Characteristics in long-term follow-up Edda Bahlmann a , Carsten Schneider a , Korff Krause a , Klaus Hertting a , Sigrid Boczor a , Thomas Wollner b , Jens-Uwe Voigt c , Karl-Heinz Kuck a,⁎ a b

Department of Cardiology, Community Hospital St. Georg, Hamburg, Germany Department of Cardiology, Community Hospital Harburg, Hamburg, Germany c Department of Cardiology, University Clinic Erlangen, Erlangen, Germany

Received 13 October 2006; received in revised form 18 December 2006; accepted 20 December 2006 Available online 3 April 2007

Abstract Tako-Tsubo Cardiomyopathy (TTC) is described as left ventricular (LV) dysfunction with the phenomenon of “apical ballooning”, rapidly resolving, without coronary artery stenoses. Methods: Fifteen patients with TTC and transthoracic echocardiography (TTE) at their admission, were reviewed (2001 to 2006). Follow-up (F/U) TTE was performed in varying intervals. To compare diameters of posterior wall (PW), interventricular septum (IVS), left atrium (LA), LV in end-diastole (LVED) and LV in end-systole (LVES) and valve insufficiencies, patients with comparable F/U are selected. Results: Fourteen patients were female (mean age 69.6 years). Angiography demonstrated LV systolic dysfunction with mean ejection fraction (EF) of 31.3%. In the acute-phase (day 0 to day 3), TTE showed a mean EF of 35.7%, not significantly different from EF obtained in angiography. Short-term F/U was performed in 9 patients after median time-interval of 20 days with an increase to a mean EF of 58.8%. F/U in 2006 has been performed in 10 patients (median time-interval 18.7 months) and showed normal EF. No significant difference in diameters of LA, LVED and LVES could be obtained comparing baseline and long-term data (p = 0.493, p = 0.790 and p = 0.275). PW and IVS were significantly thicker at baseline compared to TTE {greater than or equal to} day 62 of F/U (p = 0.003 and p = 0.026). At baseline mitral valve insufficiency (MI) was mild in 50.0% and moderate in 12.5%, mild and moderate tricuspid valve insufficiency (TI) was recognized in 50% (25% respectively). MI and TI were regredient in F/U. In three patients an intraventricular systolic flow acceleration could be detected in the acute phase. Conclusions: Characteristics of TTC, besides transient LV apical ballooning are also a significant change in LV wall thickness and reversible valve insufficiencies. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Tako-Tsubo cardiomyopathy; Apical ballooning; Echocardiography

1. Introduction The “Tako-Tsubo” (Japanese for octopus trap) Cardiomyopathy (TTC) has been first described in Japanese population in 1991 [1] and was reported to account for 1% of

⁎ Corresponding author. AK St. Georg, II. Med. Abteilung (Cardiology), Lohmühlenstraβe 5, 20099 Hamburg, Germany. Tel.: +49 40 2890 2305; fax: +49 40 2890 4444. E-mail address: [email protected] (K.-H. Kuck). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.12.090

admissions for suspected acute myocardial infarction in Japan during the past decade [2]. From 2001 on numerous case reports [3–5] and to our knowledge six series with 88 patients by a multicenter report of Tsuchihashi et al. [2] and case series of Kurisu et al. (n = 30) [6], Abe et al. (n = 17) [7], Scott et al. (n = 22) [8], Ilan et al. (n = 19) [9] and Klaus Hertting et al. (n = 32) [10] from all over the world have been published. Patients with Tako-Tsubo Cardiomyopathy typically present with the clinical signs of an acute myocardial infarction [2,7,10]. Acute myocarditis also has to be considered as differential diagnosis as it is able to mimic acute

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myocardial infarction [11]. Marked initial impairment of the ventricular systolic function of the mid and apical left ventricle, i.e., “apical ballooning” and normal coronary angiogram has been described in all cases of the literature [10,8]. The striking hallmark of the disease is its extremely rapid resolution after sudden onset [12,7]. Emotional or physical stress with sympathetic stimulation is described as its preceding triggering factors [8,9], but the aetiology and precise pathophysiologic basis in this syndrome has not yet been fully clarified [13]. The role of echocardiography in the diagnosis of apical ballooning syndrome yet has not been well established. 2. Methods We retrospectively reviewed 15 patients with the diagnosis of Tako-Tsubo Cardiomyopathy, who, despite coronary angiography, also underwent transthoracic echocardiography (TTE) within the initial hospital admission (day 0 to day 7). Diagnosis was established by left ventricular angiography (LVA) at the day of hospital admission between July 2001 and January 2006. Follow-up (F/U) echocardiography was then performed in varying time-intervals after hospital admission and the patients were followed over a long-term period. TTE imaging was performed from standard windows. Ejection fraction is measured with biplane Simpson's method. Regional wall motion abnormalities were assessed in the 17-segment model of the left ventricular chamber in all 15 patients. Left ventricular dynamic outflow tract (LVOT)

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obstruction was measured with continuous-wave Doppler. Assessment of valve regurgitation was obtained by the PISA (proximal isovelocity surface area) quantification method and was graded from trace to severe. 2.1. Statistical methods Characteristics of the cathlab procedure and initial echocardiogram (days 0–7 post cathlab) are presented as absolute values for all patients. Left ventricular myocardial segments are plotted patientwise for the initial echo showing the assessment of regional wall-motion (normal, hypokinesia, akinesia, dyskinesia). The ejection fraction is plotted patientwise over whole follow-up time using a logarithmic scale. To compare the diameters of posterior wall (PW), intraventricular septal wall (IVS), left atrium (LA), LV in enddiastole (LVED) and LV in end-systole (LVES) between early and later stage patients with comparable time schedule of follow-up are selected (Fig. 1). The resulting groups statistically analysed include 8 patients with a baseline echo (days 0–3) and a long-term follow-up echo (F/U ≥day 62) and are compared by building general linear models (GLM) for repeated measures which provide analysis of variance. Furthermore, of them a subgroup of 6 patients with additional early echo between F/U days 4–7 can be selected and as well compared by GLM. Significances are computed overall for the within-subject effect of time and also given for mean pairwise differences.

Fig. 1. Flow-chart of selected TTE F/U schedule.

Fig. 2. Coronary angiogram in a patient with apical ballooning showing normal coronary arteries. A, Right coronary artery, left anterior oblique view; B, left coronary artery, right anterior oblique view.

63/F 71/F 78/F 69/F 73/M 75/F 70/F 74/F 57/F 64/F 67/F 44/F 79/F 76/F 84/F

04-Jul-2001 09-Jul-2002 07-Jan-2003 29-Jun-2003 27-Nov-2003 13-Feb-2004 16-Jun-2004 22-Jul-2004 25-Aug-2004 03-Sep-2004 24-Sep-2004 29-Oct-2004 17-Nov-2005 28-Oct-2005 16-Jan-2006

39 25 39 25 33 36 30 36 35 28 40 30 28 25 21

SR SR Afib SR SR SR SR SR SR SR SR SR SR SR SR

1 2 1 4 0 0 1 4 2 5 0 7 0 0 0

38 40 53 30 40 38 45 35 41 46 37 41 41 37 40

45 56 51 43 55 57 53 50 50 49 48 54 49 38 49

34 43 34 21 35 46 35 30 41 25 38 29 37 28 33

24.4 23.0 33.3 51.2 36.4 19.3 33.0 40.0 18.0 49.0 20.8 46.3 24.5 26.3 32.0

35 42 40 38 45 39 30 35 31 36 38 56 28 30 35

15 13 11 12 11 12 15 11 11 11 11 11 15 16 11

13 12 11 13 11 12 14 11 12 11 10 11 15 14 10

1 2 3 2 0 0 2 1 2 2 2 0 3 1 0

1 0 1 1 0 0 0 0 0 1 0 0 0 1 2

1 2 3 3 1 0 0 1 3 1 2 0 3 0 1

37

55

50

57 34

4.10

4.03

67

35

65

EF IVS PW Grade mitral Grade aortic Grade tricuspid Systolic RV Systolic Maximal % thickness thickness valve valve valve pressure VMAX LVDP [mm] [mm] insufficiency insufficiency insufficiency [mm Hg] [cm/s] [mm Hg]

LA indicates left atrium; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; FS, fractional shortening; EF, ejection fraction; IVS, intraventricular septum; PW, posterior wall; RV, right ventricular; VMAX, maximal velocity; LVDP, left ventricular pressure gradient; MI, mitral valve insufficiency; TI, tricuspid valve insufficiency; AI, aortic valve insufficiency. Insufficiency is graded from I as trace to IVas severe.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Cathlab Rhythm Days first LA LVEDD LVESD FS EF% echo post [mm] [mm] [mm] % cathlab

Another subgroup of the initial 15 patients including 9 patients with short-term F/U between days 7–61 and the additional F/U in 2006 are each presented descriptively only because for some of the patients no comparable baseline F/U as defined by days 0–3 can be obtained. To describe continuous parameters the mean ± standard deviation, minimum and maximum vale (range) and the and percentiles (P1, P2, P3) are given. Time intervals are presented by median count of days, minimum, maximum and percentiles. The data analysis is exploratory, that is p-values are interpreted as nominal, not adjusted for multiple comparisons. A probability ≤0.05 could be interpreted as statistically significant finding.

Patient Age/ Cathlab no. gender date

Table 1 Clinical and echocardiographic features of 15 patients, presenting with clinical signs of an acute myocardial infarction

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Statistical analysis was performed with SPSS for Windows, release 11.5.2.1, SPSS Inc. 3. Results 3.1. Clinical presentation Fourteen (93%) of the patients were female. The mean age was 69.6 ± 9.9 (range 44 to 84, P1–P3: 64; 71; 76) years. All but one patient were in sinus rhythm. One patient showed atrial fibrillation on electrocardiogram. All patients were admitted at hospital with the clinical signs of an acute myocardial infarction. 3.2. Clinical testing Angiography: Left ventricular angiography was performed in all patients within 24 h after onset of symptoms. Angiogram demonstrated systolic dysfunction with the appearance of apical ballooning and substantially reduced ejection fraction (31.3 ± 6.0%; range 21 to 40; P1–P3: 25.0; 30.0; 36.0) in all cases. In coronary angiography no evidence of relevant coronary artery stenoses could be found (Fig. 2). Transthoracic echocardiography: Initial TTE was performed either on the day of coronary angiography (n = 6) or up to 7 days post cathlab with a medium time-interval of 1 day (P1–P3: 0; 1; 4). Initial patient data are presented in Table 1. The segmental distribution was focussed on the apical

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segments and in only few patients also medial segmental wall motion abnormalities were seen (Fig. 3). In the acutephase (baseline TTE) patients showed typical mid-apical left ventricular dysfunction with a mean ejection fraction of 35.7 ±5.6% (range 28 to 45%; P1–P3: 30; 35; 40). There was no significant difference in these patients compared to the obtained EF in left ventricular angiography of 31.9 ± 6.5% (range 21 to 40%; P1–P3: 25; 33; 39) (p = 0.195). Basal segments were normo- or hypercontractile at end-systole in all cases. Short-term follow-up TTE (days 7–61 post LVA) described by a median timeinterval of 20 days (range 7–43; P1–P3: 7.5; 20; 38) and showed an increase in left ventricular function with a mean EF of 58.8 ± 9.5% (range 48 to 70%; P1–P3: 48.5; 58; 70%) (Fig. 4). Comparing baseline and long-term follow-up the mean left atrial-, left ventricular end-diastolic and end-systolic diameter were measured (Fig. 5). No significant difference in LA, LVEDD and LVESD-dimensions can be detected comparing baseline and long-term data (p = 0.493, p = 0.790 and p = 0.275). Left ventricular posterior wall thickness was measured with a mean of 12.4 ± 1.8 mm at baseline TTE vs. 10.9 ± 1.9 mm at long-term F/U and enddiastolic interventricular septum diameter with a mean of 13.0 ± 2.1 mm vs. 11.5 ± 2.2 mm. Posterior and interventricular septal wall was significantly thicker in baseline TTE compared to TTE ≥ day 62 of follow-up (p = 0.003 and p = 0.026) (Fig. 6).

Fig. 3. Segmental analysis of regional wall motion abnormalities (normal, hypokinesia, akinesia, dyskinesia) in 17 left ventricular myocardial segments of 15 apical ballooning patients who had initial TTE studies obtained within 1 week after left ventricular angiography.

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Fig. 4. Ejection fraction (EF) assessed in left ventricular (LV) angiography and further follow-up TTE.

In these patients of comparable time schedules, mitral valve insufficiency was recognized as mild in 50.0% and moderate in 12.5% at baseline TTE. Mild and moderate tricuspid valve insufficiency was recognized in 50% of patients (each 25% respectively) (Fig. 7). Mitral and tricuspid valve insufficiencies were regredient in follow-up (Fig. 8). In only one patient a mild aortic valve insufficiency was seen. None of the patients had mitral or aortic valve calcifications. Of the 15 patients five patients demonstrated moderate to severe pulmonary hypertension in the initial TTE with an estimated pulmonary artery systolic pressure of N30 mm Hg (mean 46.6 ± 10.5 mm Hg) in the first available echocardiography (initial TTE). In four of these five patients with pulmonary hypertension moderate or severe mitral valve regurgitation was

present. Complete resolvement was detectable in 2 cases after 9 and 24 days respectively. In one patient a pressure decrease from 50 to 37 mm Hg between days 2 and 42 of follow-up was notable. In two of these patients no echocardiographic shortterm follow-up was performed. In long-term follow-up (≥2 months) pulmonary hypertension could not be demonstrated. Initial right heart failure was present in 4 patients. In three of these four patients control echocardiography was performed. In all three patients right heart failure was resolved at days 6, 7 and 24, of follow-up TTE of each patient. In three patients an intraventricular systolic flow acceleration with a late-peaking systolic velocity curve, is detectable in the LVOT. In these patients TTE has been performed at days 0 and 1 after hospital admission. The mean intraventricular pressure gradient in these three patients was 55.3 ± 17.6 mm

Fig. 5. Diameters of left atrium (LA), left ventricular end-diastole (LVEDD) and left ventricular end-systole (LVESD) of patients with comparable follow-up (echo at baseline 0–3 days and ≥62 days after LV angiography, n = 8). F/U, follow-up.

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Fig. 6. Posterior wall (PW) and intraventricular septal wall (IVS) thickness of patients with comparable follow-up (echo at baseline 0–3 days and ≥62 days after LV angiography, n = 8). F/U, follow-up.

Hg (absolute values: 65; 35; 66). There is a considerable moderate left ventricular hypertrophy in these three cases. A SAM (systolic anterior movement of the mitral leaflet)phenomenon was detectable in one case. There was no coexistence with a mitral valve insufficiency in this patient. Outflow

tract gradient rapidly resolved in the controlled two cases. In one patient LVOT obstruction improved from 35 mm Hg to 25 mm Hg in the control echocardiography after 27 days, in the second patient LVOT obstruction improved rapidly from 66 mm Hg to 10 mm Hg after 4 days. 3.3. Additional follow-up The additional F/U in 2006 has been performed in 10 patients after a median time-interval of 18.7 months (range 2.2 to 44.3; P1–P3: 4.2; 18.7; 26.9) after the initial clinical event and showed normal left ventricular ejection fraction in all cases (70.2 ± 0.6; range 70 to 72; P1–P3: 35.8; 39.5; 47.0). Left atrial and left ventricular dimensions were the following: LA 40.7 ± 5.7 (range 34 to 49; P1–P3: 35.8; 39.5; 47.0), LVEDD: 48.5 ± 7.3 (range 35 to 57; P1–P3: 42.3; 49.5; 56.0), LVESD: 32.5 ± 5.8 (range 21 to 41; P1–P3: 28.8; 33; 36.8), PW: 11.2 ± 1.8 (range 8–13; P1–P3: 9.8; 12.0; 13.0), IVS: 11.9 ± 2.1 (range 8 to 14; P1–P3: 10.5; 12.5; 14.0). Three patients were lost to follow-up after the initial TTE. Two patients died (lung cancer shortly after diagnosis of TTC; unknown). 4. Discussion

Fig. 7. A and B. Apical 4-chamber-view in end-systole (day of admission) demonstrating ballooning of the left ventricular apex and severe tricuspid regurgitation in colour-flow Doppler with a maximum velocity of 3.28 m/s and an estimated pulmonary artery systolic pressure of 53 mm Hg.

In our retrospective study of 15 patients, mainly women, with the diagnosis of TTC presented with the clinical signs of an acute myocardial infarction. TTC is considered as differential diagnosis for 2% of ST-segment elevation infarcts [14]. Compared to the usual forms of the acute coronary ischemia syndrome, also in our study, all patients with TTC showed a severe widespread transient balloon-like mid-apical hypo-/a-/dyskinesia, involving many coronary territories [8,10]. LV angiography and TTE, when performed in the acute phase (within 3 days) after hospital admission, demonstrated marked impairment of left ventricular function and was comparable in EF without significant difference. Initial echocardiography as a primary tool for evaluation of the diagnosis of TTC is therefore feasible. It has yet been reported in only one case series [4]. A striking hallmark of the

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Fig. 8. Grade of valve insufficiency (aortic, mitral and tricuspid valve) in patients with comparable follow-up (echo at baseline 0–3 days and ≥62 days after LV angiography, n = 8).

disease is its favourable prognosis and rapid resolution [2,8,15]. Each of our patients survived the clinical event. The wall motion abnormalities improved rapidly also in our case series and reached an almost normal left ventricular function in less than 1 month when demonstrated in follow-up. Left ventricular dimensions within the normal range, as demonstrated in our case series, in combination with mid-apical ballooning differ substantially from the typical profile of dilated cardiomyopathy (DCM) [16]. Nevertheless, endomyocardial biopsies, performed in two patients in our series, or cardiac magnetic resonance studies to exclude myocarditis were done in a limited number of cases but throughout were without evidence of an infiltrative or inflammatory process [8,6,7,9]. Whether it is indicated to perform endomyocardial biopsies in the clinical routine in patients with these myocardial disorders therefore has to be questioned. In contrast, in patients with DCM, it could be demonstrated recently that myocardial persistence of various viruses play a role in the pathogenesis of DCM far more frequently than suspected so far [16]. An additional aspect of the unique presentation of TTC, which is discussed as a possible pathophysiologic mechanism, is a hypercontraction of the basal segments with outflow tract obstruction in some cases [13,8,2]. We could demonstrate for the first time in a systematic evaluation, a

significant change in LV wall thickness comparing the acute phase TTE to follow-up. The cause of the acute LV hypertrophy remains unknown. In our study the initial dynamic LV outflow-tract obstruction was related to a moderate ventricular hypertrophy and hypercontractility of the basal segments as well as to a SAM-phenomenon, which also was described in the literature as an important factor in the development of apical ballooning [13]. In all cases the time interval between the initial coronary angiography and echocardiography was short and preceded for not over 1 day. The literature is particularly analysed to answer the question of coexisting valvular involvement, but transient mitral and tricuspid regurgitation is first described in our study. It frequently was present in our patients, although not secondary to left ventricular and mitral annular dilation. In addition, pulmonary hypertension developed in some patients in response to the elevation in left atrial pressure. Right ventricular involvement is rarely described in the literature [4,15]. 5. Conclusions Characteristics for Tako-Tsubo Cardiomyopathy, besides reversible left ventricular apical ballooning and LVOT

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obstruction, also is the additional presence of a transient incompetence of the mitral and tricuspid valves and right heart failure. Significant change in left ventricular wall thickness might play a role in the pathophysiology of this rare and prognostic favourable cardiomyopathy. Echocardiographic examination rarely can establish the aetiology of acute cardiomyopathy, even though it is instrumental both in confirming the presence of ventricular dysfunction and providing prognostic data and is especially useful, by making the diagnosis more likely, in the condition of TTC. Acknowledgements

[6]

[7]

[8]

[9]

[10]

We thank Detlef Hennig for the excellent technical assistance.

[11]

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